The recent cloning of the human opioid receptors has presented new opportunities for understanding the structure and function of the opioid receptor endorphin system and the development of novel therapeutic agents. The delta opioid receptor is a target for such drug development, because agonists acting on this receptor produce effective antinociception and appear to show a limited ability to produce many of the nontherapeutic side effects associated primarily with the mu-opioid analgesics such as morphine. The racemic compound (+/-)-BW373U86 is a potent delta-opioid receptor agonist. Radioligand binding studies show that (+/-)-BW373U86 is only about 10-fold selective for delta over mu opioid receptors. Studies of our enantiomeric forms of (+/-)-BW373U86 and derivatives (SNC80 and related compounds) show that some of these isomers show significantly improved receptor binding and pharmacological selectivity. We have now determined the binding affinities of 10 different SNC80-related compounds at cloned human delta and mu opioid receptors and measured the potency of SNC80 for the inhibition of forskolin-stimulated adenylyl cyclase. The most selective and potent delta receptor ligand (SNC162; Ki 0.625 nM) differed from SNC80 by the absence of the 3- methoxy substitution of the benzyl ring. The results of these studies define specific structural features of these compounds responsible for opioid receptor interactions and suggest a possibly novel mechanism for delta receptor activation. The abuse of cocaine is widely recognized to be an extremely serious health and social problem of epidemic proportions for which there is no effective treatment. This problem continues to be exacerbated by cocaine base ("crack") smoking, an extremely reinforcing and dependence producing route of self-administration. Our approach to the design and synthesis of drugs which might have utility for the treatment and prevention of cocaine abuse involves development of high affinity, slowly dissociating, low intrinsic activity cocaine receptor agonists. This approach has been validated with our finding that the lead compound GBR 12909 prevents cocaine self-administration in rhesus monkeys trained to self-administer cocaine with no effect on normal behavior, as measured by food maintained responding. We have now synthesized an ultra long acting analog of GBR 12935, called DLB 583. Our new drug decreased cocaine self-administration, and its effects lasted almost a month after a single dose. Thus, we have obtained a novel potential medication for the treatment and prevention of cocaine abuse.